In the past year, our efforts focus on the role of SIRT1 in hepatic and intestinal nutrient metabolism and tissue homeostasis, as well as the role of SIRT1 in ES cell biology and animal development. As a highly conserved NAD+-dependent protein deacetylase, SIRT1 has been shown as a key metabolic sensor that directly links nutrient signals to animal metabolic homeostasis. Although the functions of SIRT1 have been extensively studied in various metabolic tissues in recent years, the role of SIRT1 in nutrient absorption and sensing in small intestine, a key metabolic organ that provides the first interface between nutrients and animal metabolism, is still completely unknown. To elucidate the function of SIRT1 in intestinal metabolism, we recently generated a novel intestine-specific SIRT1 KO mouse model, SIRT1 IKO mice. SIRT1 IKO mice were morphologically normal under standard feeding conditions, however, they displayed significantly lower serum and hepatic bile acid levels than control animals, suggesting a defect in bile acid metabolism. Further analyses demonstrate that intestinal SIRT1 is an important regulator of ileal bile acid absorption that feedback modulates systemic bile acid homeostasis and cholesterol metabolism. Specific deletion of SIRT1 in intestine decreases the intestinal HNF1&#945;/FXR signaling pathway, thereby reducing expression of the bile acid transporter genes Asbt and Ost&#945;/Ost&#946;, and absorption of ileal bile acids. We provide evidence that SIRT1 regulates the HNF1&#945;/FXR signaling pathway partially through DCoH2, a dimerization cofactor of HNF1&#945;. SIRT1 deacetylates DCoH2, facilitating dimerization and DNA binding of HNF1&#945;. Furthermore, intestinal SIRT1 deficiency decreases the expression of FGF15, which in turn alleviates the inhibition of hepatic bile acid synthesis, reducing hepatic bile acid levels and decreasing liver damage upon high bile acid diets feeding. Our findings uncovered a novel function of SIRT1 in intestinal bile acid absorption and revealed a previously unknown molecular mechanism by which SIRT1 regulates the HNF1&#945;/FXR pathway. Our studies further point out that the same molecular mechanism can yield distinct pathophysiologies in the same metabolic pathway in different tissues, and suggest that tissue specificity should be considered when applying SIRT1 small molecule modulators-based therapeutic strategies to bile acid and cholesterol diseases. A manuscript describing this study was recently published (Kazgan et al., 2014, Gastroenterology). The small intestine is not only essential for nutrient absorption and sensing, but also provides the first line of defense against pathogenic microbes as well as various environmental agents such as diet, drugs, and toxins. As a result, the intestinal epithelium is under rapid renewal every 3-5 days. Therefore, intestine is a perfect system for studies on interplays between nutrient metabolism, host defense, and tissue homeostasis. We recently discovered that deletion of SIRT1 specifically in intestinal epithelial cells stimulates cellular NF-&#954;B signaling and Nrf2-mediated oxidative stress pathways, leading to hyperactivation of Paneth cells, enhanced intestinal inflammation, and altered gut microbiota. Under stress conditions induced by nutrients, chemicals, or aging, the extensive interaction between these three components increases the susceptibility to colitis. Importantly, we discovered that the mRNA levels of human SIRT1 were significantly decreased in human ulcerative colitis patients. Together with a recent report that a SIRT1 mutation that reduces its deacetylase activity is associated with colitis in humans, our findings support the hypothesis that SIRT1 is a key genetic factor that regulates the susceptibility to inflammatory bowel diseases (IBDs) in both humans and mice. This study uncovers a new role for SIRT1 in intestinal tissue homeostasis, and suggests that small molecules that activate SIRT1 maybe beneficial for treatment of human IBDs. A manuscript describing this exciting study is currently under review. In addition to being a master regulator of metabolism and inflammation, SIRT1 is also a key regulator of animal development. However, despite the fact that the developmental defects of the first SIRT1 KO mouse model was reported 11 years ago, the molecular mechanisms underlying this important function of SIRT1 remain largely unclear. Xiaoling and her group recently decided to assess the importance of SIRT1 in animal development and stem cell biology using embryonic stem cells (ESCs) and mice as models. In collaboration with Dr. Yingming Zhaos group at the University of Chicago, they identified a cellular retinoic acid binding protein, CRABPII, as a hyperacetylated protein in SIRT1 null cells in a global SILAC-based analysis of Lys acetylation. They went on to show that CRABPII is a novel deacetylation substrate of SIRT1. In a series of elegant studies, they demonstrated that SIRT1 contributes to the maintenance of homeostatic retinoic acid (RA) signaling and modulates mouse ESC differentiation in part through deacetylation of CRABPII. They discovered that RA-mediated acetylation of CRABPII at K102 is essential for its nuclear accumulation and subsequent activation of RA signaling. SIRT1 interacts with and deacetylates CRABPII, regulating its subcellular localization. As a result, SIRT1 deficiency induces hyperacetylation and nuclear accumulation of CRABPII, enhancing RA signaling and accelerating mouse ESC differentiation in response to RA. More importantly, they further found that SIRT1 deficiency induced developmental defects is associated with elevated RA signaling in mice. Their findings reveal a novel molecular mechanism that regulates RA signaling, and highlight the importance of SIRT1 in regulation of ESC pluripotency and embryogenesis. Their studies are solid and thorough, and have important implications in understanding gene-environment interactions that affect animal development. A manuscript describing this interesting story has recently been accepted for publication (Tang et al., 2014, Molecular Cell).